The long tail of oncogenic drivers in prostate cancer

Armenia, Joshua; Wankowicz, Stephanie A.; Liu, David; Gao, Jianjiong; Kundra, Ritika; Reznik, Ed; Chatila, Walid K.; Chakravarty, Debyani; Han, G. Celine; Coleman, Ilsa M.; Montgomery, Bruce; Pritchard, Colin C.; Morrissey, Colm; Barbieri, Christopher E.; Beltran, Himisha; Sboner, Andrea; Zafeiriou, Zafeiris; Miranda, Susana; Bielski, Craig M.; Penson, A.; Tolonen, Charlotte; Huang, Franklin W.; Robinson, Dan R.; Wu, Yi; Lonigro, Robert J.; Garraway, Levi A.; Demichelis, Francesca; Kantoff, Philip W.; Taplin, Mary‐Ellen; Abida, Wassim; Taylor, Barry S.; Scher, Howard I.; Nelson, Peter S.; Bono, Johann S. de; Rubin, Mark A.; Sawyers, Charles L.; Chinnaiyan, Arul M.; Schultz, Nikolaus; Allen, Eliezer M. Van

doi:10.1038/s41588-018-0078-z

Cited by 696 publications

(794 citation statements)

References 41 publications

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“…The frequency of genomic copy number alterations in our mCRPC tumors was consistent with previous exome sequencing reports (Armenia et al, 2018; Beltran et al, 2013; Grasso et al, 2012; Robinson et al, 2015) (Figure 1A, Figure S2A). The percent of the genome altered in each sample ranged between 7% and 47% (median 23%; Table S1).…”

Section: Resultssupporting

confidence: 92%

“…In contrast to previously published large-scale analyses of primary and metastatic prostate cancer that have largely focused on the coding genome (Abeshouse et al, 2015; Armenia et al, 2018; Barbieri et al, 2012; Beltran et al, 2013; Fraser et al, 2017; Robinson et al, 2015; Taylor et al, 2010; Wedge et al, 2018), we have performed whole genome analysis of metastases from 101 mCRPC patients at 109x depth of coverage in tumor samples. This coverage, two-fold deeper than previous efforts in this space (Wedge et al, 2018), and performed on a large patient cohort, has produced a unique resource for dissecting structural variation in metastatic prostate cancer samples.…”

Section: Discussionmentioning

confidence: 99%

“…A major barrier to studying mCRPC has been the difficulty in obtaining tumor samples, as clinical biopsies of metastatic lesions are not routinely performed. mCRPC has recently been evaluated by targeted or whole exome sequencing (Armenia et al, 2018; Beltran et al, 2013; Grasso et al, 2012; Robinson et al, 2015; Zehir et al, 2017). These studies identified alterations in pathways involving androgen signaling, DNA repair, and phosphoinositide 3-kinase (PI3K) signaling, as well as recurrent mutations in genes such as SPOP , FOXA1 , and IDH1 .…”

Section: Introductionmentioning

confidence: 99%

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Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Quigley

Dang

Zhao

et al. 2018

Cell

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566

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While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Quigley

Dang

Zhao

et al. 2018

Cell

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566

663

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“…This finding was further strengthened by a recent TCGA study (4), wherein a subset of PCa patients' harboring SPOPmutation/CHD1-deletion exhibits elevated DNA methylation levels accompanied with frequent events of SPINK1 overexpression. Recently, a new subtype of ETS-fusion-negative tumors has been defined by frequent mutations in the epigenetic regulators and chromatin remodelers (55). Yet another study, using genome-wide methylated DNAimmunoprecipitation sequencing revealed higher number of methylation events in TMPRSS2-ERG fusion-negative as compared to normal and TMPRSS2-ERG fusion-positive PCa specimens (14), thus collectively, these independent findings reaffirm the critical role of epigenetic pathways engaged in the pathogenesis of SPINK1+ subtype.…”

Section: Discussionsupporting

confidence: 65%

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

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PurposeSerine Peptidase Inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer (PCa) subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in PCa remains largely unknown.Experimental DesignMicroRNA-prediction tools were employed to examine the SPINK1-3’UTR for miRNAs binding. Luciferase reporter assays were performed to confirm the SPINK1-3’UTR binding of shortlisted miR-338-5p/miR-421. Further, miR-338-5p/-421 overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and mice xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. Immunohistochemistry and RNA in-situ hybridization was carried-out on PCa patients’ tissue microarray for SPINK1 and EZH2 expression respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421 regulatory regions. Bisulfite sequencing and methylated DNA-immunoprecipitation was performed on PCa cell lines and patients’ specimens.ResultsWe established a critical role of miRNA-338-5p/-421 in post-transcriptional regulation of SPINK1. Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive PCa cells abrogate oncogenic properties including cell-cycle progression, stemness and drug resistance, and show reduced tumor burden and distant metastases in mice model. Importantly, we show SPINK1-positive PCa patients exhibit increased EZH2 expression, suggesting its role in miRNA-338-5p/-421 epigenetic silencing. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive PCa cells and patients’ specimens confirms epigenetic silencing.ConclusionOur findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive PCa, while restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.TRANSLATIONAL IMPACTWe establish a regulatory model involving the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2, thereby, revealing hitherto unknown mechanism of SPINK1 up-regulation in SPINK1-positive subtype. Our findings provide a strong rationale for the development of potential therapeutic strategies for SPINK1-positive malignancies. We demonstrate that restoring miRNA-338-5p/miRNA-421 expression using epigenetic drugs including DNMTs inhibitors in combination with HDACs or HKMTs inhibitors or miRNA synthetic mimics in SPINK1-positive prostate cancer abrogate SPINK1-mediated oncogenicity. The major findings of this study will not only advance the prostate cancer field, but will also be valuable for treatment and disease management of other SPINK1-positive malignancies.

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“…The majority of SPOP mutations (~96%) detected thus far are missense heterozygous mutations that are located in the MATH domain (Cancer Genome Atlas Research Network, ; Armenia et al , ), a motif responsible for substrate recognition and interaction (Zhuang et al , ; Fig C). Similar to the findings reported previously (Zhang et al , ), SPOP hotspot mutation F133V almost completely abolished SPOP interaction with BRD4 (Fig A).…”

Section: Resultsmentioning

confidence: 99%

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

Yan

Wang

et al. 2019

EMBO Mol Med

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CULLIN3‐based E3 ubiquitin ligase substrate‐binding adaptor gene SPOP is frequently mutated in prostate cancer (PCa). PCa harboring SPOP hotspot mutants (e.g., F133V) are resistant to BET inhibitors because of aberrant elevation of BET proteins. Here, we identified a previously unrecognized mutation Q165P at the edge of SPOP MATH domain in primary and metastatic PCa of a patient. The Q165P mutation causes structural changes in the MATH domain and impairs SPOP dimerization and substrate degradation. Different from F133V hotspot mutant tumors, Q165P mutant patient‐derived xenografts (PDXs) and organoids were modestly sensitive to the BET inhibitor JQ1. Accordingly, protein levels of AR, BRD4 and downstream effectors such as RAC1 and phosphorylated AKT were not robustly elevated in Q165P mutant cells as in F133V mutant cells. However, NEO2734, a novel dual inhibitor of BET and CBP/p300, is active in both hotspot mutant (F133V) and non‐hotspot mutant (Q165P) PCa cells in vitro and in vivo. These data provide a strong rationale to clinically investigate the anti‐cancer efficacy of NEO2734 in SPOP‐mutated PCa patients.

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The long tail of oncogenic drivers in prostate cancer

Cited by 696 publications

References 41 publications

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

The novel BET‐CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild‐type prostate cancer

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